Alterations in tropomyosin isoform expression in human transitional cell carcinoma of the urinary bladder

Abstract

Previous studies of transformed rodent fibroblasts have suggested that specific isoforms of the actin-binding protein tropomyosin (TM) could function as suppressors of transformation, but an analysis of TM expression in patient tumor tissue is limited. The purpose of our study was to characterize expression of the different TM isoforms in human transitional cell carcinoma of the urinary bladder by immunohistochemistry and Western blot analysis. We found that TM1 and TM2 protein levels were markedly reduced and showed >60% reduction in 61% and 55% of tumor samples, respectively. TM5, which was expressed at very low levels in normal bladder mucosa, exhibited aberrant expression in 91% of tumor specimens. The Western blot findings were confirmed by immunohistochemical analysis in a number of tumors. We then investigated the mechanism underlying TM expression deregulation, in the T24 human bladder cancer cell line. We showed that levels of TM1, TM2 and TM3 are reduced in T24 cells, but significantly upregulated by inhibition of the mitogen-activated protein kinase-signaling pathway. In addition, inhibition of this pathway was accompanied by restoration of stress fibers. Overall, changes in TM expression levels seem to be an early event during bladder carcinogenesis. We conclude that alterations in TM isoform expression may provide further insight into malignant transformation in transitional cell carcinomas of the bladder and may be a useful target for early detection strategies. © 2004 Wiley-Liss, Inc. Key words: tropomyosin; cytoskeleton; bladder neoplasmsTransitional cell carcinoma (TCC) is the most common cancer type of the urinary bladder, representing approximately 90% of all cases. More than 57,000 people are diagnosed with TCC of the urinary bladder each year in the United States alone, and 12,500 of these patients are expected to die from the cancer. 1 Cytoscopy is the most valuable method to detect and monitor TCC, but it remains difficult to predict tumor progression, optimal therapy and finally clinical outcome. 2,3 There is a clear need for developing biomarkers for bladder cancer management.Alterations of the actin-based cytoskeleton are an established part of the neoplastic phenotype, and it is now demonstrated that such alteration is not a byproduct of cellular transformation but contributes to malignant transformation. 4,5 These alterations in actin remodeling are associated with downregulation of numerous actin-binding proteins and cell adhesion molecules, which are therefore candidate markers for early cancer detection and prognostic indication. 6 Tropomyosins (TMs) are a family of actin-binding proteins essential for the integrity of actin filaments. 7 Although TMs have been known to function in regulation of muscle contraction, the functional significance of the multiple TM isoforms present in non-muscle cells has remained largely unclear. Several studies have suggested that specific isoforms of TMs may possess tumor suppressor activity. Consistent with this hypothesis it was shown that (i) expr...

Clinical and tumor significance of tropomyosin-1 expression levels in renal cell carcinoma

“…However, the existence of other TPM family members varied among the different types of cancers or studies (17)(18)(19). In the present study, TPM1 was significantly downregulated in most RCC tissues compared to that in the tumor adjacent normal renal tissues while TPM2-4 showed no significant expression differences in the RCC tissue samples.…”

Resensitization of breast cancer cells to anoikis by Tropomyosin-1: role of Rho kinase-dependent cytoskeleton and adhesion

“…Work from this and other laboratories has identified that the tropomyosin isoform-1 (TM1), is consistently suppressed in breast cancer cell lines (Bhattacharya et al, 1990) and breast tumors (Raval et al, 2003), and is downregulated in urinary bladder tumors (Pawlak et al, 2004), suggesting that the loss of TM1 may contribute to the neoplastic transformation. Restoration of TM1 expression in several oncogene-transformed (Prasad et al, 1993(Prasad et al, , 1999Braverman et al, 1996) and spontaneously transformed breast cancer cells (Mahadev et al, 2002;Raval et al, 2003) reorganizes microfilaments, forms stress fibers in a Rho-kinase-dependent fashion (Shah et al, 2001) and suppresses the anchorage-independent growth.…”

Differential tissue-specific protein markers of vaginal carcinoma

“…The loss of tropomyosin expression in tumour cells may prevent proper assembly of microfilaments and, thereby contribute to the invasive and metastatic properties of cancer cells (Shah et al, 2001). In bladder carcinoma alterations in TM expression (reduced TM1, 2 and 3) seem to be an early event in bladder carcinogenesis (Pawlak et al, 2004). Similar to our findings, low expression of TM1 and TM2 has been detected in cervical carcinoma (Bae et al, 2005), of TM2 in oesophageal squamous cell carcinoma (Jazii et al, 2006) and of TM1 in breast carcinoma (Franzen et al, 1996;Raval et al, 2003).…”